Medical image synthesis presents unique challenges due to the inherent complexity and high-resolution details required in clinical contexts. Traditional generative architectures such as Generative Adversarial Networks (GANs) or Variational Auto Encoder (VAEs) have shown great promise for high-resolution image generation but struggle with preserving fine-grained details that are key for accurate diagnosis. To address this issue, we introduce Pixel Perfect MegaMed, the first vision-language foundation model to synthesize images at resolutions of 1024x1024. Our method deploys a multi-scale transformer architecture designed specifically for ultra-high resolution medical image generation, enabling the preservation of both global anatomical context and local image-level details. By leveraging vision-language alignment techniques tailored to medical terminology and imaging modalities, Pixel Perfect MegaMed bridges the gap between textual descriptions and visual representations at unprecedented resolution levels. We apply our model to the CheXpert dataset and demonstrate its ability to generate clinically faithful chest X-rays from text prompts. Beyond visual quality, these high-resolution synthetic images prove valuable for downstream tasks such as classification, showing measurable performance gains when used for data augmentation, particularly in low-data regimes. Our code is accessible through the project website - https://tehraninasab.github.io/pixelperfect-megamed.
Text-to-image generative models have achieved remarkable breakthroughs in recent years. However, their application in medical image generation still faces significant challenges, including small dataset sizes, and scarcity of medical textual data. To address these challenges, we propose Med-Art, a framework specifically designed for medical image generation with limited data. Med-Art leverages vision-language models to generate visual descriptions of medical images which overcomes the scarcity of applicable medical textual data. Med-Art adapts a large-scale pre-trained text-to-image model, PixArt-$\alpha$, based on the Diffusion Transformer (DiT), achieving high performance under limited data. Furthermore, we propose an innovative Hybrid-Level Diffusion Fine-tuning (HLDF) method, which enables pixel-level losses, effectively addressing issues such as overly saturated colors. We achieve state-of-the-art performance on two medical image datasets, measured by FID, KID, and downstream classification performance.
Evaluating generative models for synthetic medical imaging is crucial yet challenging, especially given the high standards of fidelity, anatomical accuracy, and safety required for clinical applications. Standard evaluation of generated images often relies on no-reference image quality metrics when ground truth images are unavailable, but their reliability in this complex domain is not well established. This study comprehensively assesses commonly used no-reference image quality metrics using brain MRI data, including tumour and vascular images, providing a representative exemplar for the field. We systematically evaluate metric sensitivity to a range of challenges, including noise, distribution shifts, and, critically, localised morphological alterations designed to mimic clinically relevant inaccuracies. We then compare these metric scores against model performance on a relevant downstream segmentation task, analysing results across both controlled image perturbations and outputs from different generative model architectures. Our findings reveal significant limitations: many widely-used no-reference image quality metrics correlate poorly with downstream task suitability and exhibit a profound insensitivity to localised anatomical details crucial for clinical validity. Furthermore, these metrics can yield misleading scores regarding distribution shifts, e.g. data memorisation. This reveals the risk of misjudging model readiness, potentially leading to the deployment of flawed tools that could compromise patient safety. We conclude that ensuring generative models are truly fit for clinical purpose requires a multifaceted validation framework, integrating performance on relevant downstream tasks with the cautious interpretation of carefully selected no-reference image quality metrics.
Counterfactual medical image generation effectively addresses data scarcity and enhances the interpretability of medical images. However, due to the complex and diverse pathological features of medical images and the imbalanced class distribution in medical data, generating high-quality and diverse medical images from limited data is significantly challenging. Additionally, to fully leverage the information in limited data, such as anatomical structure information and generate more structurally stable medical images while avoiding distortion or inconsistency. In this paper, in order to enhance the clinical relevance of generated data and improve the interpretability of the model, we propose a novel medical image generation framework, which generates independent pathological and structural features based on causal disentanglement and utilizes text-guided modeling of pathological features to regulate the generation of counterfactual images. First, we achieve feature separation through causal disentanglement and analyze the interactions between features. Here, we introduce group supervision to ensure the independence of pathological and identity features. Second, we leverage a diffusion model guided by pathological findings to model pathological features, enabling the generation of diverse counterfactual images. Meanwhile, we enhance accuracy by leveraging a large language model to extract lesion severity and location from medical reports. Additionally, we improve the performance of the latent diffusion model on long-tailed categories through initial noise optimization.
We present seg2med, a modular framework for anatomy-driven multimodal medical image synthesis. The system integrates three components to enable high-fidelity, cross-modality generation of CT and MR images based on structured anatomical priors. First, anatomical maps are independently derived from three sources: real patient data, XCAT digital phantoms, and synthetic anatomies created by combining organs from multiple patients. Second, we introduce PhysioSynth, a modality-specific simulator that converts anatomical masks into prior volumes using tissue-dependent parameters (e.g., HU, T1, T2, proton density) and modality-specific signal models. It supports simulation of CT and multiple MR sequences including GRE, SPACE, and VIBE. Third, the synthesized anatomical priors are used to train 2-channel conditional denoising diffusion models, which take the anatomical prior as structural condition alongside the noisy image, enabling generation of high-quality, structurally aligned images. The framework achieves SSIM of 0.94 for CT and 0.89 for MR compared to real data, and FSIM of 0.78 for simulated CT. The generative quality is further supported by a Frechet Inception Distance (FID) of 3.62 for CT synthesis. In modality conversion, seg2med achieves SSIM of 0.91 for MR to CT and 0.77 for CT to MR. Anatomical fidelity evaluation shows synthetic CT achieves mean Dice scores above 0.90 for 11 key abdominal organs, and above 0.80 for 34 of 59 total organs. These results underscore seg2med's utility in cross-modality synthesis, data augmentation, and anatomy-aware medical AI.
This study presents Latent Diffusion Autoencoder (LDAE), a novel encoder-decoder diffusion-based framework for efficient and meaningful unsupervised learning in medical imaging, focusing on Alzheimer disease (AD) using brain MR from the ADNI database as a case study. Unlike conventional diffusion autoencoders operating in image space, LDAE applies the diffusion process in a compressed latent representation, improving computational efficiency and making 3D medical imaging representation learning tractable. To validate the proposed approach, we explore two key hypotheses: (i) LDAE effectively captures meaningful semantic representations on 3D brain MR associated with AD and ageing, and (ii) LDAE achieves high-quality image generation and reconstruction while being computationally efficient. Experimental results support both hypotheses: (i) linear-probe evaluations demonstrate promising diagnostic performance for AD (ROC-AUC: 90%, ACC: 84%) and age prediction (MAE: 4.1 years, RMSE: 5.2 years); (ii) the learned semantic representations enable attribute manipulation, yielding anatomically plausible modifications; (iii) semantic interpolation experiments show strong reconstruction of missing scans, with SSIM of 0.969 (MSE: 0.0019) for a 6-month gap. Even for longer gaps (24 months), the model maintains robust performance (SSIM > 0.93, MSE < 0.004), indicating an ability to capture temporal progression trends; (iv) compared to conventional diffusion autoencoders, LDAE significantly increases inference throughput (20x faster) while also enhancing reconstruction quality. These findings position LDAE as a promising framework for scalable medical imaging applications, with the potential to serve as a foundation model for medical image analysis. Code available at https://github.com/GabrieleLozupone/LDAE
Counterfactual medical image generation enables clinicians to explore clinical hypotheses, such as predicting disease progression, facilitating their decision-making. While existing methods can generate visually plausible images from disease progression prompts, they produce silent predictions that lack interpretation to verify how the generation reflects the hypothesized progression -- a critical gap for medical applications that require traceable reasoning. In this paper, we propose Interpretable Counterfactual Generation (ICG), a novel task requiring the joint generation of counterfactual images that reflect the clinical hypothesis and interpretation texts that outline the visual changes induced by the hypothesis. To enable ICG, we present ICG-CXR, the first dataset pairing longitudinal medical images with hypothetical progression prompts and textual interpretations. We further introduce ProgEmu, an autoregressive model that unifies the generation of counterfactual images and textual interpretations. We demonstrate the superiority of ProgEmu in generating progression-aligned counterfactuals and interpretations, showing significant potential in enhancing clinical decision support and medical education. Project page: https://progemu.github.io.
Text-to-image diffusion models have demonstrated a remarkable ability to generate photorealistic images from natural language prompts. These high-resolution, language-guided synthesized images are essential for the explainability of disease or exploring causal relationships. However, their potential for disentangling and controlling latent factors of variation in specialized domains like medical imaging remains under-explored. In this work, we present the first investigation of the power of pre-trained vision-language foundation models, once fine-tuned on medical image datasets, to perform latent disentanglement for factorized medical image generation and interpolation. Through extensive experiments on chest X-ray and skin datasets, we illustrate that fine-tuned, language-guided Stable Diffusion inherently learns to factorize key attributes for image generation, such as the patient's anatomical structures or disease diagnostic features. We devise a framework to identify, isolate, and manipulate key attributes through latent space trajectory traversal of generative models, facilitating precise control over medical image synthesis.
Vision-Language Foundation Models (VLFM) have shown a tremendous increase in performance in terms of generating high-resolution, photorealistic natural images. While VLFMs show a rich understanding of semantic content across modalities, they often struggle with fine-grained alignment tasks that require precise correspondence between image regions and textual descriptions a limitation in medical imaging, where accurate localization and detection of clinical features are essential for diagnosis and analysis. To address this issue, we propose a multi-stage architecture where a pre-trained VLFM provides a cursory semantic understanding, while a reinforcement learning (RL) algorithm refines the alignment through an iterative process that optimizes for understanding semantic context. The reward signal is designed to align the semantic information of the text with synthesized images. We demonstrate the effectiveness of our method on a medical imaging skin dataset where the generated images exhibit improved generation quality and alignment with prompt over the fine-tuned Stable Diffusion. We also show that the synthesized samples could be used to improve disease classifier performance for underrepresented subgroups through augmentation.
Despite the potential of synthetic medical data for augmenting and improving the generalizability of deep learning models, memorization in generative models can lead to unintended leakage of sensitive patient information and limit model utility. Thus, the use of memorizing generative models in the medical domain can jeopardize patient privacy. We propose a framework for identifying replicas, i.e. nearly identical copies of the training data, in synthetic medical image datasets. Our REpLIca deteCTion (RELICT) framework for medical image generative models evaluates image similarity using three complementary approaches: (1) voxel-level analysis, (2) feature-level analysis by a pretrained medical foundation model, and (3) segmentation-level analysis. Two clinically relevant 3D generative modelling use cases were investigated: non-contrast head CT with intracerebral hemorrhage (N=774) and time-of-flight MR angiography of the Circle of Willis (N=1,782). Expert visual scoring was used as the reference standard to assess the presence of replicas. We report the balanced accuracy at the optimal threshold to assess replica classification performance. The reference visual rating identified 45 of 50 and 5 of 50 generated images as replicas for the NCCT and TOF-MRA use cases, respectively. Image-level and feature-level measures perfectly classified replicas with a balanced accuracy of 1 when an optimal threshold was selected for the NCCT use case. A perfect classification of replicas for the TOF-MRA case was not possible at any threshold, with the segmentation-level analysis achieving a balanced accuracy of 0.79. Replica detection is a crucial but neglected validation step for the development of generative models in medical imaging. The proposed RELICT framework provides a standardized, easy-to-use tool for replica detection and aims to facilitate responsible and ethical medical image synthesis.
Data scarcity in medical imaging poses significant challenges due to privacy concerns. Diffusion models, a recent generative modeling technique, offer a potential solution by generating synthetic and realistic data. However, questions remain about the performance of convolutional neural network (CNN) models on original and synthetic datasets. If diffusion-generated samples can help CNN models perform comparably to those trained on original datasets, reliance on patient-specific data for training CNNs might be reduced. In this study, we investigated the effectiveness of diffusion models for generating synthetic medical images to train CNNs in three domains: Brain Tumor MRI, Acute Lymphoblastic Leukemia (ALL), and SARS-CoV-2 CT scans. A diffusion model was trained to generate synthetic datasets for each domain. Pre-trained CNN architectures were then trained on these synthetic datasets and evaluated on unseen real data. All three datasets achieved promising classification performance using CNNs trained on synthetic data. Local Interpretable Model-Agnostic Explanations (LIME) analysis revealed that the models focused on relevant image features for classification. This study demonstrates the potential of diffusion models to generate synthetic medical images for training CNNs in medical image analysis.
The generation of medical images presents significant challenges due to their high-resolution and three-dimensional nature. Existing methods often yield suboptimal performance in generating high-quality 3D medical images, and there is currently no universal generative framework for medical imaging. In this paper, we introduce the 3D Medical Diffusion (3D MedDiffusion) model for controllable, high-quality 3D medical image generation. 3D MedDiffusion incorporates a novel, highly efficient Patch-Volume Autoencoder that compresses medical images into latent space through patch-wise encoding and recovers back into image space through volume-wise decoding. Additionally, we design a new noise estimator to capture both local details and global structure information during diffusion denoising process. 3D MedDiffusion can generate fine-detailed, high-resolution images (up to 512x512x512) and effectively adapt to various downstream tasks as it is trained on large-scale datasets covering CT and MRI modalities and different anatomical regions (from head to leg). Experimental results demonstrate that 3D MedDiffusion surpasses state-of-the-art methods in generative quality and exhibits strong generalizability across tasks such as sparse-view CT reconstruction, fast MRI reconstruction, and data augmentation.
Generative models trained on multi-institutional datasets can provide an enriched understanding through diverse data distributions. However, training the models on medical images is often challenging due to hospitals' reluctance to share data for privacy reasons. Federated learning(FL) has emerged as a privacy-preserving solution for training distributed datasets across data centers by aggregating model weights from multiple clients instead of sharing raw data. Previous research has explored the adaptation of FL to generative models, yet effective aggregation algorithms specifically tailored for generative models remain unexplored. We hereby propose a novel algorithm aimed at improving the performance of generative models within FL. Our approach adaptively re-weights the contribution of each client, resulting in well-trained shared parameters. In each round, the server side measures the distribution distance between fake images generated by clients instead of directly comparing the Fr\'echet Inception Distance per client, thereby enhancing efficiency of the learning. Experimental results on three public chest X-ray datasets show superior performance in medical image generation, outperforming both centralized learning and conventional FL algorithms. Our code is available at https://github.com/danny0628/FedCAR.
Medical image segmentation has recently demonstrated impressive progress with deep neural networks, yet the heterogeneous modalities and scarcity of mask annotations limit the development of segmentation models on unannotated modalities. This paper investigates a new paradigm for leveraging generative models in medical applications: controllably synthesizing data for unannotated modalities, without requiring registered data pairs. Specifically, we make the following contributions in this paper: (i) we collect and curate a large-scale radiology image-text dataset, MedGen-1M, comprising modality labels, attributes, region, and organ information, along with a subset of organ mask annotations, to support research in controllable medical image generation; (ii) we propose a diffusion-based data engine, termed MRGen, which enables generation conditioned on text prompts and masks, synthesizing MR images for diverse modalities lacking mask annotations, to train segmentation models on unannotated modalities; (iii) we conduct extensive experiments across various modalities, illustrating that our data engine can effectively synthesize training samples and extend MRI segmentation towards unannotated modalities.
Generative models have proven to be very effective in generating synthetic medical images and find applications in downstream tasks such as enhancing rare disease datasets, long-tailed dataset augmentation, and scaling machine learning algorithms. For medical applications, the synthetically generated medical images by such models are still reasonable in quality when evaluated based on traditional metrics such as FID score, precision, and recall. However, these metrics fail to capture the medical/biological plausibility of the generated images. Human expert feedback has been used to get biological plausibility which demonstrates that these generated images have very low plausibility. Recently, the research community has further integrated this human feedback through Reinforcement Learning from Human Feedback(RLHF), which generates more medically plausible images. However, incorporating human feedback is a costly and slow process. In this work, we propose a novel approach to improve the medical plausibility of generated images without the need for human feedback. We introduce IMPROVE:Improving Medical Plausibility without Reliance on Human Validation - An Enhanced Prototype-Guided Diffusion Framework, a prototype-guided diffusion process for medical image generation and show that it substantially enhances the biological plausibility of the generated medical images without the need for any human feedback. We perform experiments on Bone Marrow and HAM10000 datasets and show that medical accuracy can be substantially increased without human feedback.
We introduce Mediffusion -- a new method for semi-supervised learning with explainable classification based on a joint diffusion model. The medical imaging domain faces unique challenges due to scarce data labelling -- insufficient for standard training, and critical nature of the applications that require high performance, confidence, and explainability of the models. In this work, we propose to tackle those challenges with a single model that combines standard classification with a diffusion-based generative task in a single shared parametrisation. By sharing representations, our model effectively learns from both labeled and unlabeled data while at the same time providing accurate explanations through counterfactual examples. In our experiments, we show that our Mediffusion achieves results comparable to recent semi-supervised methods while providing more reliable and precise explanations.
Variational autoencoder (VAE) is one of the most common techniques in the field of medical image generation, where this architecture has shown advanced researchers in recent years and has developed into various architectures. VAE has advantages including improving datasets by adding samples in smaller datasets and in datasets with imbalanced classes, and this is how data augmentation works. This paper provides a comprehensive review of studies on VAE in medical imaging, with a special focus on their ability to create synthetic images close to real data so that they can be used for data augmentation. This study reviews important architectures and methods used to develop VAEs for medical images and provides a comparison with other generative models such as GANs on issues such as image quality, and low diversity of generated samples. We discuss recent developments and applications in several medical fields highlighting the ability of VAEs to improve segmentation and classification accuracy.
Alzheimers disease progresses slowly and involves complex interaction between various biological factors. Longitudinal medical imaging data can capture this progression over time. However, longitudinal data frequently encounter issues such as missing data due to patient dropouts, irregular follow-up intervals, and varying lengths of observation periods. To address these issues, we designed a diffusion-based model for 3D longitudinal medical imaging generation using single magnetic resonance imaging (MRI). This involves the injection of a conditioning MRI and time-visit encoding to the model, enabling control in change between source and target images. The experimental results indicate that the proposed method generates higher-quality images compared to other competing methods.
Synthetic Data Generation (SDG) based on Artificial Intelligence (AI) can transform the way clinical medicine is delivered by overcoming privacy barriers that currently render clinical data sharing difficult. This is the key to accelerating the development of digital tools contributing to enhanced patient safety. Such tools include robust data-driven clinical decision support systems, and example-based digital training tools that will enable healthcare professionals to improve their diagnostic performance for enhanced patient safety. This study focuses on the clinical evaluation of medical SDG, with a proof-of-concept investigation on diagnosing Inflammatory Bowel Disease (IBD) using Wireless Capsule Endoscopy (WCE) images. Its scientific contributions include a) a novel protocol for the systematic Clinical Evaluation of Medical Image Synthesis (CEMIS); b) a novel variational autoencoder-based model for the generation of high-resolution synthetic WCE images; and c) a comprehensive evaluation of the synthetic images using the CEMIS protocol by 10 international WCE specialists, in terms of image quality, diversity, and realism, as well as their utility for clinical decision-making. The results show that TIDE-II generates clinically plausible, very realistic WCE images, of improved quality compared to relevant state-of-the-art generative models. Concludingly, CEMIS can serve as a reference for future research on medical image-generation techniques, while the adaptation/extension of the architecture of TIDE-II to other imaging domains can be promising.
The scarcity of publicly available medical imaging data limits the development of effective AI models. This work proposes a memory-efficient patch-wise denoising diffusion probabilistic model (DDPM) for generating synthetic medical images, focusing on CT scans with lung nodules. Our approach generates high-utility synthetic images with nodule segmentation while efficiently managing memory constraints, enabling the creation of training datasets. We evaluate the method in two scenarios: training a segmentation model exclusively on synthetic data, and augmenting real-world training data with synthetic images. In the first case, models trained solely on synthetic data achieve Dice scores comparable to those trained on real-world data benchmarks. In the second case, augmenting real-world data with synthetic images significantly improves segmentation performance. The generated images demonstrate their potential to enhance medical image datasets in scenarios with limited real-world data.